Partial or full A1 agonists - N6 heterocyclic 5&#39; thio substituted adenosine derivatives

ABSTRACT

N 6  heterocyclic 5′ modified adenosine derivatives that are adenosine A 1  receptor partial or full agonists, and as such, are useful for modifying cardiac activity, modifying adipocyte function, treating central nervous system disorders, and treating diabetic disorders and obesity in mammals, and especially in humans.

BACKGROUND OF THE INVENTION

(1) Field of the Invention

This invention includes stable and useful drugs and pro-drugs that areN⁶ heterocyclic 5′-thio modified adenosine derivatives. The compositionsof this invention are selective, partial or full adenosine A₁ receptoragonists, and as such, are useful for modifying cardiac activity,modifying adipocyte function, treating central nervous system disorders,and treating diabetic disorders and obesity in mammals, and especiallyin humans.

(2) Description of the Art

There are at least two subtypes of adenosine receptors in the heart: A₁and A_(2A). Each subtype affects different physiological functions. TheA₁ adenosine receptor mediates two distinct physiological responses.Inhibition of the cardiostimulatory effects of catecholamine aremediated via the inhibition of adenylate cyclase, whereas the directeffects to slow the heart rate (HR) and to prolong impulse propagationthrough the AV node are due in great part to activation of I_(KAdo). (B.Lerman and L. Belardinelli Circulation, Vol. 83 (1991), P 1499-1509 andJ. C. Shryock and L. Belardinelli The Am. J. Cardiology, Vol. 79 (1997)P 2-10). Both, the anti-β-adrenergic action and direct depressanteffects on SA and AV nodal function are mediated by the A₁ receptor;there is no role for the A_(2A) receptor in this response to adenosine.A_(2A) receptors mediate the coronary vasodilatation caused byadenosine. Stimulation of the A₁ adenosine receptor accordingly shortensthe duration and decreases the amplitude of the action potential of AVnodal cells, and hence prolongs the refractory period of the AV nodalcell. The consequence of these effects is to limit the number ofimpulses conducted from the atria to the ventricles. This forms thebasis of the clinical utility of A₁ receptor agonists for the treatmentof supraventricular tachycardias, including termination of nodalre-entrant tachycardias, and control of ventricular rate during atrialfibrillation and flutter.

A clinical utility of A₁ agonists therefore is in the treatment of acuteand chronic disorders of heart rhythm, especially those diseasescharacterized by rapid heart rate where the rate is driven byabnormalities in the sinoatrial, atria, and AV nodal tissues. Suchdisorders include but are not limited to atrial fibrillation,supraventricular tachycardia and atrial flutter. Exposure to A₁ agonistscauses a reduction in the heart rate and a regularization of theabnormal rhythm thereby improving cardiovascular function.

A₁ agonists, through their ability to inhibit the effects ofcatecholamines, decrease cellular cAMP, and thus, should have beneficialeffects in the failing heart where increased sympathetic tone increasescellular cAMP levels. The latter has been shown to be associated withincreased likelihood of ventricular arrhythmias and sudden death. All ofthe above concepts are discussed in reviews regarding the effects ofadenosine on cardiac electrophysiology (see B. Lerman and L.Belardinelli Circulation, Vol. 83 (1991), P 1499-1509 and J. C. Shryockand L. Belardinelli, Am. J. Cardiology, Vol. 79 (1997) P 2-10).

A controversial area in the field of A₁ adenosine agonism is that thebenefit of preconditioning of the heart prior to ischemia may be due tobinding of adenosine to the A₁ receptor. Evidence for this hypothesiscomes from a rabbit ischemia model wherein2-chloro-N6-cyclopentyladenosine (CCPA) and R-PIA were administeredprior to ischemia providing protection with respect to infarct size (J.D. Thornton et al. Circulation Vol. 85 (1992) 659-665).

A₁ agonists, as a result of their inhibitory action on cyclic AMPgeneration, have antilipolytic effects in adipocytes that leads to adecreased release of nonesterified fatty acids (NEFA) (E. A. van Schaicket al J. Pharmacokinetics and Biopharmaceutics, Vol. 25 (1997) p 673-694and P. Strong Clinical Science Vol. 84 (1993) p. 663-669).Non-insulin-dependent diabetes mellitus (NIDDM) is characterized by aninsulin resistance that results in hyperglycemia. Factors contributingto the observed hyperglycemia are a lack of normal glucose uptake andactivation of skeletal muscle glycogen synthase (GS). Elevated levels ofNEFA have been shown to inhibit insulin-stimulated glucose uptake andglycogen synthesis (D. Thiebaud et al Metab. Clin. Exp. Vol. 31 (1982) p1128-1136 and G. Boden et al J. Clin. Invest. Vol. 93 (1994) p2438-2446). The hypothesis of a glucose fatty acid cycle was proposed byP. J. Randle as early as 1963 (P. J. Randle et al Lancet (1963) p.785-789). A tenet of this hypothesis would be that limiting the supplyof fatty acids to the peripheral tissues should promote carbohydrateutilization (P. Strong et al Clinical Science Vol. 84 (1993) p.663-669).

The benefit of an A₁ agonist in central nervous disorders has beenreviewed and the content are included herein by reference (L. J. S.Knutsen and T. F. Murray In Purinergic Approaches in ExperimentalTherapeutics, Eds. K. A. Jacobson and M. F. Jarvis (1997) Wiley-Liss,N.Y., P-423-470). Briefly, based on experimental models of epilepsy, amixed A_(2A):A₁ agonist, metrifudil, has been shown to be a potentanticonvulsant against seizures induced by the inverse benzodiazepineagonist methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM,H. Klitgaard Eur. J. Pharmacol. (1993) Vol. 224 p. 221-228). In otherstudies using CGS 21680, an A_(2A) agonist, it was concluded that theanticonvulsant activity was attributed to activation of the A₁ receptor(G. Zhang et al. Eur. J. Pharmacol. Vol. 255 (1994) p. 239-243).Furthermore, A₁ adenosine selective agonists have been shown to haveanticonvulsant activity in the DMCM model (L. J. S. Knutsen In Adenosineand Adenne Nucleotides: From Molecular Biology to IntegrativePhysiology; eds. L. Belardinelli and A. Pelleg, Kluwer: Boston, 1995, pp479-487). A second area where an A₁ adenosine agonist has a benefit isin animal models of forebrain ishemia as demonstrated by Knutsen et al(J. Med. Chem. Vol. 42 (1999) p. 3463-3477). The benefit inneuroprotection is believed to be in part due to the inhibition of therelease of excitatory amino acids (ibid).

There are a number of full A₁ agonists disclosed in the prior art.However, the agonists disclosed are generally in the forms that are notuseful in the mammalian body. Because useful forms of A₁ agonists maynot always be stable, soluble or they may have other properties thatmake their incorporation into therapeutic dosage forms difficult, it isoften necessary to identify compositions that are more easilyincorporated into therapeutic dosage forms in order to provide thedesired therapeutic effect. Also, these agonists fail as usefultherapeutics due to side effects caused by the non-selective stimulationof the A₁ adenosine receptor in all biologically available tissues andthe desensitization of the desired response preempting their use aschronic agents. Therefore, there remains a need for specific andselective A₁ agonists, precursors and/or pro-drugs that are converted inthe body into useful therapeutic compositions.

SUMMARY OF THE INVENTION

In one aspect, this invention includes heterocyclic 5′-thio modifiedadenosine derivative compositions that are useful partial or fulladenosine A₁ receptor agonists.

In another aspect, this invention includes pharmaceutical compositionsincluding one or more heterocyclic 5′-thio modified adenosine derivativecompositions that are well tolerated with few side effects.

In still another embodiment, this invention includes heterocyclic5′-thio modified adenosine derivatives having the formula:

In yet another embodiment, this invention includes methods foradministering compositions of this invention to mammals, and especiallyto humans, to stimulate coronary activity, to modify adipocyte function,to treat central nervous system disorders, and to treat diabeticdisorders.

In a further embodiment, this invention is pharmaceutical compositionsof matter comprising at least one composition of this invention and oneor more pharmaceutical excipients.

DESCRIPTION OF THE CURRENT EMBODIMENT

This intention includes a class of heterocyclic 5′-thio modifiedadenosine derivatives having the formula having the formula:

-   -   wherein X¹═S, S(O), S(O2);    -   wherein R¹ is a monocyclic or polycyclic heterocyclic group        containing from 3 to 15 carbon atoms wherein at least one carbon        atom is substituted with an atom or molecule selected from the        group consisting of N, O, P and S—(O)₀₋₂ and wherein R¹ does not        contain an epoxide group, and wherein R₂ is selected from the        group consisting of hydrogen, halo, CF₃, and cyano; wherein R₃        and R₄ are independently selected from the group consisting of        hydrogen, and —(CO)—R′ and —(CO)—R″ wherein R′ and R″ are        independently selected from the group consisting of C₁₋₁₅ alkyl,        C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl, heterocyclyl, aryl, and        heteroaryl, which alkyl, alkenyl, alkynyl, aryl, heterocyclyl,        and heteroaryl are optionally substituted with 1 to 3        substituents independently selected from the group of halo, NO₂,        heterocyclyl, aryl, heteroaryl, CF₃, CN, OR²⁰, SR²⁰, S(O)R²²,        SO₂R²², SO₂N(R²⁰)₂, SO₂NR²⁰COR²², SO₂NR²⁰CO₂R²²,        SO₂NR²⁰CON(R²⁰)₂, N(R²⁰)₂, NR²⁰COR²², NR²⁰CO₂R²², NR²⁰CON(R²⁰)₂,        NR²⁰C(NR²⁰)NHR²³, COR²⁰, CO₂R²⁰, CON(R²⁰)₂, CONR²⁰SO₂R²²,        NR²⁰SO₂R²², SO₂NR²⁰CO₂R²², OCONR²⁰SO₂R²², OC(O)R²⁰,        C(O)OCH₂OC(O)R²⁰, and OCON(R²⁰)₂ and each optional heteroaryl,        aryl, and heterocyclyl substituent is optionally substituted        with halo, NO₂, alkyl, CF₃, amino, mono- or di-alkylamino, alkyl        or aryl or heteroaryl amide, NR²⁰COR²², NR²⁰SO₂R²², COR²⁰,        CO₂R²⁰, CON(R²⁰)₂, NR²⁰CON(R²⁰)₂, OC(O)R²⁰, OC(O)N(R²⁰)₂, SR²⁰,        S(O)R²², SO₂R²², SO₂NR²⁰), CN, or OR²⁰;    -   wherein R₅ is selected from the group consisting of C₁₋₁₅ alkyl,        C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl, heterocyclyl, aryl, and        heteroaryl, wherein alkyl, alkenyl, alkynyl, aryl, heterocyclyl,        and heteroaryl are optionally substituted with 1 to 3        substituents independently selected from the group consisting of        halo, alkyl, NO₂, heterocyclyl, aryl, heteroaryl, CF₃, CN, OR²⁰,        SR²⁰, S(O)₂R²⁰, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, SO₂NR²⁰COR²²,        SO₂NR²⁰CO₂R²², SO₂NR²⁰CON(R²⁰)₂, P(O)(OR²⁰)₂, N(R²⁰)₂,        NR²⁰COR²², NR²⁰CO₂R²², NR²⁰CON(R²⁰)₂, NR²⁰C(NR²⁰)NHR²³, COR²⁰,        CO₂R²⁰, CON(R²⁰)₂, CONR²⁰SO₂R²², NR²⁰SO₂R²², SO₂NR²⁰CO₂R²²,        OCONR²⁰SO₂R²², OC(O)R²⁰, C(O)OCH₂OC(O)R²⁰, and OCON(R²⁰)₂ and        wherein optional heteroaryl, aryl, and heterocyclyl substituent        is optionally substituted with halo, NO₂, alkyl, CF₃, amino,        mono- or di-alkylamino, alkyl or aryl or heteroaryl amide,        NR²⁰COR²², NR²⁰SO₂R²², COR²⁰, CO₂R²°, CON(R²⁰)₂, NR²⁰CON(R²⁰)₂,        OC(O)R²⁰, OC(O)N(R²⁰), SR²⁰, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, CN, or        OR²⁰;    -   wherein R²⁰ is a member selected from the group consisting of H,        C1-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, heterocyclyl, aryl,        and heteroaryl, which alkyl, alkenyl, alkynyl, heterocyclyl,        aryl, and heteroaryl are optionally substituted with 1 to 3        substituents independently selected from halo, alkyl, mono- or        dialkylamino, alkyl or aryl or heteroaryl amide, CN, O-C1-C6        alkyl, CF3, aryl, and heteroaryl; and    -   R²² is a member selected from the group consisting of C₁₋₁₅        alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl, heterocyclyl, aryl, and        heteroaryl, which alkyl, alkenyl, alkynyl, heterocyclyl, aryl,        and heteroaryl are optionally substituted with 1 to 3        substituents independently selected from halo, alkyl, mono- or        dialkylamino, alkyl or aryl or heteroaryl amide, CN, O—C₁₋₆        alkyl, CF₃, and heteroaryl.

In preferred compositions, X¹═S or SO₂; R₂ is a hydrogen; R₃ and R₄ areeach independently selected from the group consisting of hydrogen.—(CO)—R′ and —(CO)—R″ wherein R′ and R″ are each independently selectedfrom the group consisting of C₁₋₆ alkyl and, more preferably, R₃ and R₄are each hydrogen; R₅ is selected from the group consisting of C₁₋₅alkyl, and aryl wherein alkyl, and aryl are optionally substituted withfrom 1 to 2 substituents independently selected from the groupconsisting of halo, alkyl, aryl, heteroaryl, CF₃, CN, OR²⁰, S(O)R²²,SO₂R²², SO₂N(R²⁰)₂, NR²⁰CON(R²⁰)₂, CO₂R²⁰, CON(R²⁰)₂, and wherein eachoptional heteroaryl, and aryl substituent is further optionallysubstituted with halo, alkyl, CF₃, CO₂R²⁰, CN, and OR²⁰; R₂₀ is selectedfrom the group consisting of H, C₁₋₆ alkyl; and R₂₂ is selected from thegroup consisting of C₁₋₆. In the above compositions, R₅ is morepreferably selected from the group consisting of C₁₋₈ alkyl, and arylwherein alkyl, and aryl are optionally substituted with from 1 to 2substituents independently selected from the group consisting of halo,alkyl, CF₃, and OR²⁰.

In more preferred compositions, X¹═S or SO₂; R₂ is a hydrogen; R₃ and R₄are independently selected from the group consisting of hydrogen,—(CO)—R′ and —(CO)—R″ wherein R′ and R″ are each independently selectedfrom the group consisting of C₁₋₆ alkyl which alkyl are optionallysubstituted with 1 substituent selected from the group consisting ofaryl, CF₃, CN, OR²⁰, N(R²⁰)₂, and wherein each optional aryl substituentis further optionally substituted with halo, NO₂, alkyl, CF₃; R₅ is C₁₋₅alkyl, wherein alkyl, is optionally substituted with from 1 to 2substituents independently selected from the group consisting of halo,alkyl, aryl, heteroaryl, CF₃, CN, OR²⁰, S(O)R²², SO₂R²², SO₂N(R²⁰)₂,NR²⁰CON(R²⁰)₂, CO₂R²⁰, CON(R²⁰)₂, wherein each optional heteroaryl, and,aryl substituent is further optionally substituted with halo, alkyl,CF₃, CO₂R²⁰, CN, and OR²⁰; R²⁰ is selected from the group consisting ofH, C₁₋₆ alkyl; and R₂₂ is selected from the group consisting of C₁₋₆. Inthe above compositions, R₅ is more preferably C₁₋₈ alkyl that isoptionally substituted with from 1 to 2 substituents independentlyselected from the group consisting of aryl, heteroaryl, OR²⁰, S(O)R²²,CO₂R²⁰, CON(R²⁰)₂, and wherein each optional heteroaryl, and arylsubstituent is further optionally substituted with halo, alkyl. CF₃,CO₂R²⁰, CN, and OR²⁰, and R₅ is even more preferably C₁₋₈ alkyl that isoptionally substituted with 1 substituent selected from the groupconsisting of CO₂R²⁰, and CON(R²⁰)₂, and R₅ is even more preferably C₁₋₆alkyl and most preferably methyl or ethyl or isopropyl. Also in theabove compositions, R₃ and R₄ are more preferably each hydrogen and R₂₀is more preferably selected from the group consisting of H, and methyl.

In another class of preferred compositions, R₂ is a hydrogen; R₃ and R₄are each independently selected from the group consisting of hydrogen,—(CO)—R′ and —(CO)—R″ wherein each R′ and R″ are independently selectedfrom the group consisting of C₁₋₆ alkyl, and aryl, which alkyl and arylare optionally substituted with from 1 to 2 substituents independentlyselected from the group of halo, NO₂, aryl, CF₃, CN, OR²⁰, N(R²¹)₂,S(O)R²². SO₂R²², and wherein each optional aryl substituent is furtheroptionally substituted with halo, NO₂, alkyl, CF₃; R₅ is selected fromthe group consisting of, aryl, and heteroaryl, wherein aryl, andheteroaryl are optionally substituted with from 1 to 3 substituentsindependently selected from the group consisting of halo, alkyl, aryl,heteroaryl, CF₃, CN, OR²⁰, SR²⁰, N(R²⁰)₂, S(O)R²², SO₂R²², SO₂N(R²⁰)₂,NR²⁰CO₂R²², NR²⁰CON(R²⁰)₂, CO₂R²⁰, CON(R²⁰)₂, and wherein each optionalheteroaryl, and aryl substituent is further optionally substituted withhalo, alkyl, CF₃, CO₂R²⁰, CON(R²⁰)₂, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, CN, orOR²⁰; R²⁰ is selected from the group consisting of H C₁₋₆ alkyl, andaryl, which alkyl and aryl are optionally substituted with 1 substituentselected from halo, alkyl, mono- or dialkylamino, CN, O—C₁₋₆ alkyl, CF₃;and R²² is selected from the group consisting of C₁₋₆ alkyl and aryl,which alkyl and aryl are optionally substituted with 1 substituentselected from halo, alkyl or CN, O—C₁₋₆ alkyl, and CF₃. In the abovecompositions, X¹ is preferably S; R₃ and R₄ are more preferablyhydrogen; R₅ is more preferably selected from the group consisting of,aryl, and heteroaryl, wherein aryl, and heteroaryl are optionallysubstituted with from 1 to 3 substituents independently selected fromthe group consisting of halo, alkyl, CF₃, CN, OR²⁰, SR²⁰, CO₂R²⁰,CON(R²⁰)₂. Even more preferably R₅ is aryl that is optionallysubstituted with from 1 to 2 substituents independently selected fromthe group consisting of halo, alkyl, CF₃, OR²⁰, CO₂R²⁰, CON(R²⁰)₂. Andmost preferably, R₅ is phenyl that is optionally substituted with asubstituent selected from the group consisting of methoxy, chloro,fluoro, methyl, and trifluoromethyl. In the compounds above, R²⁰ ispreferably selected from the group consisting of H, C₁₋₃ alkyl and mostpreferably H or methyl while R₂₂ is preferably selected from the groupconsisting of C₁₋₆ alkyl.

In the compositions of this invention, R₁ is preferably mono orpolysubstituted with one or more compounds selected from the groupconsisting of halogen, oxo, hydroxyl, lower alkyl, substituted loweralkyl, alkoxy, aryl, acyl, aryloxy, carboxyl, substituted aryl,heterocycle, heteroaryl, substituted heteroaryl, cycloalkyl, substitutedcycloalkyl, nitro, cyano and mixtures thereof. More preferably, R₁ is amonocyclic, bicyclic, or tricyclic cycloalkyl group containing from 3 to15 carbon atoms wherein at least one carbon atom is substituted with anatom or molecule selected from the group consisting of O or S—(O)₀₋₂.Some examples of preferred R₁ moieties include:

wherein R₁′, R₁″, R₁′″, and R₁″″ may each individually be selected fromthe group halogen, hydroxyl, lower alkyl, substituted lower alkyl,alkoxy, aryl, acyl, aryloxy, carboxyl, substituted aryl, heterocycle,heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl,nitro, and cyano, and X is O, or S(—O)₀-2, alternately, R₁′″ and R₁″″may be a single oxygen atom. More preferably, R₁′, R₁″, R₁′″, and R₁″″are each individually selected from the group hydrogen, lower alkyl, andsubstituted lower alkyl. In the compositions above, each R isindividually selected from the group consisting of H, lower alkyl, andsubstituted lower alkyl and wherein X is O, or S(—O)₀₋₂.

Most preferred compounds of this invention include,2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-(methylthiomethyl)oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5[(Ethylthio)methyl]oxolane-3,4-diol:2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(Methylethylthio)methyl]oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-(phenylthiomethyl)oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(4-Methoxyphenylthio)methyl]oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(4-chlorophenylthio)methyl]oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(4-fluorophenylthio)methyl]oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(4-methylphenylthio)methyl]oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(4-(trifluoromethyl)phenylthio)methyl]oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(2-Methoxyphenylthio)methyl]oxolane-3,4-diol;(5-{6-[((3R)oxolan-3-yl)amino]purinyl-9-yl}(2S,3S,4R,5R)-3,4-dihydroxyoxolan-2-yl)(ethylsulfonyl)methane:2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(2,4-difluorophenylthio)methyl]oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(2,6-dichlorophenylthio)methyl]oxolane-3,4-diol;2-{6-[((3R))oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(3-fluorophenylthio)methyl]oxolane-3.4-diol,2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(2-fluorophenylthio)methyl]oxolane-3,4-diol;5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(2S,3R,4R,5R)-4-acetyloxy-2-[(fluorophenylthio)methyl]oxolan-3-ylacetate; Methyl2[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(2S,3S,4R,5R)-3,4-dihydroxyoxolan-2-yl)methylthio]benzoate;{2[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(2S,3S,4R,5R)-3,4-dihydroxyoxolan-2-yl)methylthio]phenyl}-N-methylcarboxamidebenzoate;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-(benzoxazol-2-ylthiomethyl)oxolane-3,4-diol;2-{6-[((3S)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(1-methylimidazol-2-yl-thio)methyl]oxolane-3,4-diol;2-{6-[((3S)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-(pyrimidine-2-ylthiomethyl)oxolane-3,4-diol;2-{6-[((3S)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-(2-pyridylthiomethyl)oxolane-3,4-diol;2-{6-[((3S)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-(4-pyridylthiomethyl)oxolane-3,4-diol;and5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(2S,3R,4R,5R)-4-acetyloxy-2-[(4-fluorophenylthio)methyl]oxolan-3-yl]acetate.

The following definitions apply to terms as used herein.

“Halo” or “Halogen”—alone or in combination means all halogens, that is,chloro (Cl), fluoro (F), bromo (Br), iodo (I).

“Hydroxyl” refers to the group —OH.

“Thiol” or “mercapto” refers to the group —SH.

“Alkyl”—alone or in combination means an alkane-derived radicalcontaining from 1 to 20, preferably 1 to 15, carbon atoms (unlessspecifically defined). It is a straight chain alkyl, branched alkyl orcycloalkyl. Preferably, straight or branched alkyl groups containingfrom 1-15, more preferably 1 to 8, even more preferably 1-6, yet morepreferably 1-4 and most preferably 1-2, carbon atoms, such as methyl,ethyl, propyl, isopropyl, butyl, t-butyl and the like. The term “low-eralkyl” is used herein to describe the straight chain alkyl groupsdescribed immediately above. Preferably, cycloalkyl groups aremonocyclic, bicyclic or tricyclic ring systems of 3-8, more preferably3-6, ring members per ring, such as cyclopropyl, cyclopentyl,cyclohexyl, adamantyl and the like. Alkyl also includes a straight chainor branched alkyl group that contains or is interrupted by a cycloalkylportion. The straight chain or branched alkyl group is attached at anyavailable point to produce a stable compound. Examples of this include,but are not limited to 4-(isopropyl)-cyclohexylethyl or2-methyl-cyclopropylpentyl. A substituted alkyl is a straight chainalkyl, branched alkyl, or cycloalkyl group defined previously,independently substituted with 1 to 3 groups or substituents of halo,hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, acyloxy,aryloxy, heteroaryloxy, amino optionally mono- or di-substituted withalkyl, aryl or heteroaryl groups, amidino, urea optionally substitutedwith alkyl, aryl, heteroaryl or heterocyclyl groups, aminosulfonyloptionally N-mono- or N,N-di-substituted with alkyl, aryl or heteroarylgroups, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino,alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, or thelike.

“Alkenyl”—alone or in combination means a straight, branched, or cyclichydrocarbon containing 2-20, preferably 2-17, more preferably 2-10, evenmore preferably 2-8, most preferably 2-4, carbon atoms and at least one,preferably 1-3, more preferably 1-2, most preferably one carbon tocarbon double bond. In the case of a cycloalkyl group, conjugation ofmore than one carbon to carbon double bond is not such as to conferaromaticity to the ring. Carbon to carbon double bonds may be eithercontained within a cycloalkyl portion, with the exception ofcyclopropyl, or within a straight chain or branched portion. Examples ofalkenyl groups include ethenyl, propenyl, isopropenyl, butenyl,cyclohexenyl, cyclohexenylalkyl and the like. A substituted alkenyl isthe straight chain alkenyl, branched alkenyl or cycloalkenyl groupdefined previously, independently substituted with 1 to 3 groups orsubstituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl,alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono-or di-substituted with alkyl, aryl or heteroaryl groups, amidino, ureaoptionally substituted with alkyl, aryl, heteroaryl or, heterocyclylgroups, aminosulfonyl optionally N-mono- or N,N-di-substituted w ithalkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino,heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino,heteroarylcarbonylamino, carboxy, alkoxycarbonyl, aryloxycarbonyl,heteroaryloxycarbonyl, or the like attached at any available point toproduce a stable compound.

“Alkynyl”—alone or in combination means a straight or branchedhydrocarbon containing 2-20, preferably 2-17, more preferably 2-10, evenmore preferably 2-8, most preferably 2-4, carbon atoms containing atleast one, preferably one, carbon to carbon triple bond. Examples ofalkynyl groups include ethynyl, propynyl, butynyl and the like. Asubstituted alkynyl refers to the straight chain alkynyl or branchedalkenyl defined previously, independently substituted with 1 to 3 groupsor substituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl,alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono-or di-substituted with alkyl, aryl or heteroaryl groups, amidino, ureaoptionally substituted with alkyl, aryl, heteroaryl or heterocyclylgroups, aminosulfonyl optionally N-mono- or N,N-di-substituted withalkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino,heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino,heteroarylcarbonylamino, or the like attached at any available point toproduce a stable compound.

“Alkyl alkenyl” refers to a group —R—CR′═CR′″R″″, where R is loweralkyl, or substituted lower alkyl, R′, R′″, R″″ may independently behydrogen, halogen, lower alkyl, substituted lower alkyl, acyl, aryl,substituted aryl, hetaryl, or substituted hetaryl as defined below.

“Alkyl alkynyl” refers to a groups —RC CR′ where R is lower alkyl orsubstituted lower alkyl, R′is hydrogen, lower alkyl, substituted loweralkyl, acyl, aryl, substituted aryl, hetaryl, or substituted hetaryl asdefined below.

“Alkoxy” denotes the group —OR, where R is lower alkyl, substitutedlower alkyl, acyl, aryl, substituted aryl, aralkyl, substituted aralkyl,heteroalkyl, heteroarylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, or substituted cycloheteroalkyl as defined.

“Alkylthio” denotes the group —SR, —S(O)_(n=1-2)—R, where R is loweralkyl, substituted lower alkyl, aryl, substituted aryl, aralkyl orsubstituted aralkyl as defined herein.

“Acyl” denotes groups —C(O)R, where R is hydrogen, lower alkylsubstituted lower alkyl, aryl, substituted aryl and the like as definedherein.

“Aryloxy” denotes groups —OAr, where Ar is an aryl, substituted aryl,heteroaryl, or substituted heteroaryl group as defined herein.

“Amino” denotes the group NRR′, where R and R′ may independently byhydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl,hetaryl, or substituted hetaryl as defined herein or acyl.

“Amido” denotes the group —C(O)NRR′, where R and R′ may independently byhydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl,hetaryl, substituted hetaryl as defined herein.

“Carboxyl” denotes the group —C(O)OR, where R is hydrogen, lower alkyl,substituted lower alkyl, aryl, substituted aryl, hetaryl, andsubstituted hetaryl as defined herein.

“Aryl”—alone or in combination means phenyl or naphthyl optionallycarbocyclic fused with a cycloalkyl of preferably 5-7, more preferably5-6, ring members and/or optionally substituted with 1 to 3 groups orsubstituents of halo, hydroxy, alkoxy, alkylthio, alkylsulfinyl,alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, amino optionally mono-or di-substituted with alkyl, aryl or heteroaryl groups, amidino, ureaoptionally substituted with alkyl, aryl, heteroaryl or heterocyclylgroups, aminosulfonyl optionally N-mono- or N,N-di-substituted withalkyl, aryl or heteroaryl groups, alkylsulfonylamino, arylsulfonylamino,heteroarylsulfonylamino, alkylcarbonylamino, arylcarbonylamino,heteroarylcarbonylamino, or the like.

“Substituted aryl” refers to aryl optionally substituted with one ormore functional groups, e.g., halogen, lower alkyl, lower alkoxy,alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl, aryloxy,heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol,sulfamido and the like.

“Heterocycle” refers to a saturated, unsaturated, or aromaticcarbocyclic group having a single ring (e.g., morpholino, pyridyl orfuryl) or multiple condensed rings (e.g., naphthpyridyl, quinoxalyl,quinolinyl, indolizinyl or benzo[b]thienyl) and having at least onehetero atom, such as N, O or S, within the ring, which can optionally beunsubstituted or substituted with, e.g., halogen, lower alkyl, loweralkoxy; alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl,aryloxy, heterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol,sulfamido and the like.

“Heteroaryl”—alone or in combination means a monocyclic aromatic ringstructure containing 5 or 6 ring atoms, or a bicyclic aromatic grouphaving 8 to 10 atoms, containing one or more, preferably 1-4, morepreferably 1-3, even more preferably 1-2, heteroatoms independentlyselected from the group O, S, and N, and optionally substituted with 1to 3 groups or substituents of halo, hydroxy, alkoxy, alkylthio,alkylsulfinyl, alkylsulfonyl, acyloxy, aryloxy, heteroaryloxy, aminooptionally mono- or di-substituted with alkyl, aryl or heteroarylgroups, amidino, urea optionally substituted with alkyl, aryl,heteroaryl or heterocyclyl groups, aminosulfonyl optionally N-mono- orN,N-di-substituted with alkyl, aryl or heteroaryl groups,alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino,alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, or thelike. Heteroaryl is also intended to include oxidized S or N, such assulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. A carbon ornitrogen atom is the point of attachment of the heteroaryl ringstructure such that a stable aromatic ring is retained. Examples ofheteroaryl groups are pyridinyl, pyridazinyl, pyrazinyl, quinazolinyl,purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, oxazolyl,thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl,tetrazolyl, imidazolyl, triazinyl, furanyl, benzofuryl, indolyl and thelike. A substituted heteroaryl contains a substituent attached at anavailable carbon or nitrogen to produce a stable compound.

“Heterocyclyl”—alone or in combination means a non-aromatic cycloalkylgroup having from 5 to 10 atoms in which from 1 to 3 carbon atoms in thering are replaced by heteroatoms of O, S or N, and are optionally benzofused or fused heteroaryl of 5-6 ring members and/or are optionallysubstituted as in the case of cycloalkyl. Heterocycyl is also intendedto include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of atertiary ring nitrogen. The point of attachment is at a carbon ornitrogen atom. Examples of heterocyclyl groups are tetrahydrofuranyl,dihydropyridinyl, piperidinyl, pyrrolidinyl, piperazinyl,dihydrobenzofuryl, dihydroindolyl, and the like. A substitutedhetercyclyl contains a substituent nitrogen attached at an availablecarbon or nitrogen to produce a stable compound.

“Substituted heteroaryl” refers to a heterocycle optionally mono or polysubstituted with one or more functional groups, e.g., halogen, loweralkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl,hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl,substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

“Aralkyl” refers to the group —R—Ar where Ar is an aryl group and R islower alkyl or substituted lower alkyl group. Aryl groups can optionallybe unsubstituted or substituted with, e.g., halogen, lower alkyl,alkoxy, alkylthio, acetylene, amino, amido, carboxyl, hydroxyl, aryl,aryloxy, heterocycle, substituted heterocycle, hetaryl, substitutedhetaryl, nitro, cyano, thiol, sulfamido and the like.

“Heteroalkyl” refers to the group —R-Het where Het is a heterocyclegroup and R is a lower alkyl group. Heteroalkyl groups can optionally beunsubstituted or substituted with e.g., halogen, lower alkyl, loweralkoxy, alkylthio, acetylene, amino, amido, carboxyl, aryl, aryloxy,heterocycle, substituted heterocycle, hetaryl, substituted hetaryl,nitro, cyano, thiol, sulfamido and the like.

“Heteroarylalkyl” refers to the group —R-HetAr where HetAr is anheteroaryl group and R lower alkyl or substituted lower alkyl.Heteroarylalkyl groups can optionally be unsubstituted or substitutedwith, e.g., halogen, lower alkyl, substituted lower alkyl, alkoxy,alkylthio, acetylene, aryl, aryloxy, heterocycle, substitutedheterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol,sulfamido and the like.

“Cycloalkyl” refers to a divalent cyclic or polycyclic alkyl groupcontaining 3 to 15 carbon atoms.

“Substituted cycloalkyl” refers to a cycloalkyl group comprising one ormore substituents with, e.g., halogen, lower alkyl, substituted loweralkyl, alkoxy, alkylthio, acetylene, aryl, aryloxy, heterocycle,substituted heterocycle, hetaryl, substituted hetaryl, nitro, cyano,thiol, sulfamido and the like.

“Cycloheteroalkyl” refers to a cycloalkyl group wherein one or more ofthe ring carbon atoms is replaced with a heteroatom (e.g., N. O, S orP).

Substituted cycloheteroalkyl” refers to a cycloheteroalkyl group asherein defined which contains one or more substituents, such as halogen,lower alkyl, lower alkoxy, alkylthio, acetylene, amino, amido, carboxyl,hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl,substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

“Alkyl cycloalkyl” denotes the group —R-cycloalkyl where cycloalkyl is acycloalkyl group and R is a lower alkyl or substituted lower alkyl.Cycloalkyl groups can optionally be unsubstituted or substituted withe.g. halogen, lower alkyl, lower alkoxy, alkylthio, acetylene, amino,amido, carboxyl, hydroxyl, aryl, aryloxy, heterocycle, substitutedheterocycle, hetaryl, substituted hetaryl, nitro, cyano, thiol,sulfamido and the like.

“Alkyl cycloheteroalkyl” denotes the group —R-cycloheteroalkyl where Ris a lower alkyl or substituted lower alkyl. Cycloheteroalkyl groups canoptionally be unsubstituted or substituted with e.g., halogen, loweralkyl, lower alkoxy, alkylthio, amino, amido, carboxyl, acetylene,hydroxyl, aryl, aryloxy, heterocycle, substituted heterocycle, hetaryl,substituted hetaryl, nitro, cyano, thiol, sulfamido and the like.

The compounds of this invention can be prepared as outlined in theschemes 1-5 below. A general outline for the preparation of V and VI isshown in Scheme 1. Compound I can be prepared, following the proceduresreported earlier (U.S. Pat. No. 5,789,416, the specification of which isincorporated herein by reference), by reacting 6-chloropurine riboside 1with a primary amine R¹NH₂. The 2′, 3′ hydroxy groups can be protectedas acetonide by reacting I with 2,2′-dimethoxypropane in the presence ofa catalytic amount of TsOH [Evans, Parrish and Long Carbohydrat. Res.,3, 453 (1967)] to give II. Activation of the 5′-hydroxyl of II with MsClin pyridine can give the 5′-mesylate III. Displacement of the5′-mesylate with R⁵SNa can give sulfides with the general formula IV.Treatment of IV with an acid can free the 2′, 3′ hydroxyl groups to givesulfide derivatives with the general formula V. Esterification of V canafford 2′, 3′ diesters with the general formula VI.

The 2-substituted derivatives with the general formula XV can beprepared as shown in Scheme 2. Condensation of1,2,3,5-tetraacetylribofuranaside 2 with 2-substituted-6-chloropurineVII can give 2-substituted-6-chloropurineriboside triacetate VIII whichon reaction with a primary amine R¹NH, can give2-substituted-6-alkylamino derivatives IX. Hydrolysis of the acetatesfollowed by protection of the 2′, 3′ hydroxy groups as an acetonide cangive XI. Activation of the 5′-hydroxyl of XI with MsCl in pyridine cangive the 5′-mesylate XII. Displacement of the 5′-mesylate with R⁵SNa cangive sulfides with the general

formula XIII that can be deprotected to give sulfides with generalformula XIV. Esterification at the 2′, 3′ positions can afford the 2′,3′ diesters with the general formula XV.

Oxidation of sulfides with the general formula V, VI, XIV, XV (Scheme 3)with an oxidizing agent (Drabowicz, et.al. The chemistry of sulfones andsulfoxides, Wiley, New York, 1988, 233-378) can afford correspondingsulfoxides with the general formula XVI, XVII, XVIII, XIX. Thesesulfoxides on further oxidation can afford sulfones with the generalformula XX, XXI, XXII, XXIII.

An example of a specific synthesis of one of the compounds of thisinvention is shown in Scheme 4. Preparation of compound 7 starting fromcompound 3 is shown in scheme 3. Compound 3 was prepared from6-chloropurineriboside 1 and 3-(R)-aminotetrahydrofuran following theprocedure reported previously (See U.S. Pat. No. 5,789,164). Protectionof the 2′ and 3′ hydroxyls with dimethoxypropane in the presence ofTsOH(cat.) gave acetonide 4. Reaction of 4 with MsCl in pyridine at 0°C. gave mesylate 5 which on displacement with sodium methanethiolate inan acetonitrile/water mixture gave sulfide 6. Deprotection of 6 with 80%acetic acid/water gave the target compound 7.

Oxidation of the ethyl sulfide 8 with oxone (Trost, B. M.; Curran, D. P.Tetrahedron Letters 1981, 22, 1287) in MeOH gave sulfone 9 (Scheme 5).

This invention also includes pro-drugs of the A₁ agonist Compositions ofthis invention. A pro-drug is a drug which has been chemically modifiedand may be biologically inactive at its site of action, but which willbe degraded or modified by one or more enzymatic or in vivo processes tothe bioactive form. The pro-drugs of this invention should have adifferent pharmacokinetic profile to the parent enabling improvedabsorption across the mucosal epithelium, better salt formulation and/orsolubility and improved systemic stability. The compounds of thisinvention may be preferably modified at one or more of the hydroxylgroups to form pro-drugs. The modifications may be (1) ester orcarbamate derivatives which may be cleaved by esterases or lipases, forexample; (2) peptides which may be recognized by specific or nonspecific proteinase; or (3) derivatives that accumulate at a site ofaction through membrane selection or a pro-drug form or modifiedpro-drug form, or any combination of (1) to (3) above.

If a compound of this invention contains a basic group, thencorresponding acid addition salt may be prepared. Acid addition salts ofthe compounds are prepared in a standard manner in a suitable solventfrom the parent compound and an excess of acid, such as hydrochloric,hydrobromic, sulfuric, phosphoric, acetic, maleic, succinic, ormethanesulfonic. The hydrochloric salt form is especially useful. If acompound of this invention contains an acidic group, then correspondingcationic salts may be prepared. Typically the parent compound is treatedwith an excess of an alkaline reagent, such as hydroxide, carbonate oralkoxide, containing the appropriate cation. Cations such as Na⁺, K⁺,Ca⁻² and NH₄ ⁻ are examples of cations present in pharmaceuticallyacceptable salts. Certain of the compounds form inner salts orzwitterions which may also be acceptable.

The compositions of this invention are useful for treating a variety ofmammalian disorders and preferably human disorders that are mediated byan A₁ adenosine receptor. For example, the compositions of thisinvention are useful for modifying cardiac activity in mammalsexperiencing a coronary electrical disorder that can be treated bystimulating an A, adenosine receptor. Examples of coronary electricaldisorders that can be treated by the compositions of this inventioninclude supraventricular tachycardias, atrial fibrillation, atrialflutter, and AV nodal re-entrant tachycardia. Furthermore, orally activeA₁ agonists of this invention that demonstrate an excellent safetyprofile in treating supraventricular arrhythmias may also be used as aprophylactic for those at high risk of a myocardial ischemia.

The compositions of this invention are also useful for modifyingadipocyte function by stimulating an A₁ adenosine receptor that leads todiminished release of NEFA and increased release of leptin. Diseasestates related to adipocyte function that can be modified usingcompositions of this invention include diabetes, and obesity.

In skeletal muscle cells, A₁ AdoR agonists mediate a synergisticstimulation of glucose uptake and transport by insulin (Vergauwen, L. etal, J. Clin. Invest. 1994, 93, 974-81; Challiss, R. A. et al, Eur. J.Pharacol., 1992, 226, 121-8). Another therapeutic utility ofcompositions of this invention is more efficient regulation of glucoseand a decrease of circulating insulin in patients afflicted withdiabetes.

The A₁ receptor agonist. R-PIA, has been shown to increase the leptinreleased from white adipocytes and augment insulin-stimulated leptinproduction (M. Ozeck Master's Thesis Univ. of Florida 1999 with L.Belardinelli). Evidence suggests that catecholamines inhibit theproduction of leptin from adipocytes through activation of β-adrenergicreceptors. The anti-β-adrenergic effects of A₁ agonists on theadipocytes are believed to play a role in the increased release ofleptin. The functional role of leptin is multifaceted includingdecreased appetite, stimulated energy utilization, and increasedfertility.

The compositions of this invention may also be used to provide centralnervous system neuroprotection by stimulating an A₁ adenosine receptor.Central nervous system disorders that may be treated using thecompositions of this invention include epilepsy, and stroke.

In the kidney, there is evidence that stimulation of the A₁ AdoRpromotes sodium retention, promotes exchange of sodium in urine forpotassium, and reduces glomerular filtration rate as sodium excretionincreases (Gellai, M. et al, JPET, 1998, 286, 1191-6; Wilcox, C. S. etal, J. Am. Soc. Nephrol., 1999, 10, 714-720). It is believed that theseresponses are elicited by chronic local production of adenosine. Thatis, in the kidney there is a tonic effect of adenosine to stimulate theA₁ AdoR. Another clinical utility of compositions of this invention,therefore, is the selective antagonism of the A₁ AdoR in the kidney toinhibit sodium retention, inhibit the exchange of sodium for potassium,and preserve kidney glomerular filtration rate when sodium excretionrises to yield a potassium sparring diuretic that preserves renalfunction.

The compositions of this invention are further useful for providingcardiomyocyte protection from ischemic events by stimulating an A₁adenosine receptor. Ischemic events treatable using the compositions ofthis invention include stable angina, unstable angina cardiactransplant, and myocardial infarction.

An important aspect of compounds of this invention is that each compoundhas an intrinsic efficacy associated with it (for a discussion see T. P.Kenakin Stimulus Response Mechanisms. In Pharmacological Analysis ofDrug-Receptor Interaction, Ed. Kenakin, T. P. New York: Raven Press, p39-68). This intrinsic efficacy is not defined by it's affinity for thereceptor, but it is defined as the quantitative effect of the compoundto activate a given effector system (eg. cAMP production) in a givencell type. The intrinsic efficacy of a given compound may vary from celltype to cell type and/or from effector system to effector system. When acompound has an intrinsic efficacy lower than a full agonist (i.e.submaximal) than the agonist is called a partial agonist. Thus, apartial agonist is a molecule that binds to a receptor and elicits aresponse that is smaller than that of a full agonist (submaximal), butalso competitively antagonizes the response(s) elicited by a fullagonist. The tonic action of adenosine with respect to kidney functionis a prime example where a partial A₁ agonist be expected to act asantagonists (e.g. adenosine). The tonic action of adenosine with respectto kidney function is a prime example where a partial A₁ agonist couldbe expected to act as an antagonist. The compounds of this invention arebelieved to have therapeutically useful affinities for the adenosine A₁receptor, and they will have a range of intrinsic efficacies from fullagonist to partial agonist. That is, some compounds may have no effectwith respect to a given effector system in a given cell type, but be afull agonist in another cell type and/or effector system. The reason forsuch variable pharmacological behavior relates to the magnitude of thereceptor reserve for the A₁ adenosine receptor in any given cell type(eg. AV nodal cells vs. adipocytes) and for a given response. Thereceptor reserve (spare receptor capacity) is the total number ofreceptors minus the fraction of receptors that is required to induce themaximal response using a full agonist (L. E. Limbird, Cell SurfaceReceptors: A Short Course on Theory and Methods, Kluwer Acad. Pub. 1996,Boston, Mass.). Therefore, the agonist could be a full agonist ateliciting a response, and a partial agonist for eliciting anotherresponse in other tissue or cells and still be an antagonist or lackactivity for a third response in another tissue or cell. Consequently, apartial agonist targeted to a selected target is likely to cause fewerside effects than a full agonist. As a corollary, a full agonist elicitsall the effects mediated by the respective receptor, % whereas this isnot necessarily the case of a partial agonist. The compounds of thisinvention based on their affinity for the A₁ receptor and their potencyand selectivity to elicit A₁ receptor mediated responses have thepotential for therapeutic intervention in the multiple disease statesdescribed above.

Partial A₁ agonists may have an added benefit for chronic therapybecause they will be less likely to induce desensitization of the A₁receptor (R. B. Clark, B. J. Knoll, R. Barber TiPS, Vol. 20 (1999) p.279-286) and to cause side effects. Chronic administration of a fullagonist (R-N6-phenylisopropyladenosine, R-PIA) for 7 days led to adesensitization of the A₁ receptor in terms of the dromotropic responsein guinea pigs (note: a decrease in receptor number was observed—D. M.Dennis, J. C. Shryock, L. Belardinelli JPET, Vol. 272 (1995) p.1024-1035). The A₁ agonist induced inhibitory effect on the productionof cAMP by adenylate cyclase in adipocytes has been shown to desensitizeupon chronic treatment with an A₁ agonist as well (W. J. Parsons and G.L. Stiles J. Biol. Chem. Vol. 262 (1987) p. 841-847).

The compositions of this invention may be administered orally,intravenously, through the epidermis, bolus, nasally, by inhalation orby any other means known in the art for administering a therapeuticagents. The method of treatment comprises the administration of aneffective quantity of the chosen compound, preferably dispersed in apharmaceutical carrier. Dosage units of the active ingredient aregenerally selected from the range of 0.01 to 100 mg/kg, but will bereadily determined by one skilled in the art depending upon the route ofadministration, age and condition of the patient.

Pharmaceutical compositions including the compounds of this invention,and/or derivatives thereof, may be formulated as solutions orlyophilized powders for parenteral administration. Powders may bereconstituted by addition of a suitable diluent or otherpharmaceutically acceptable carrier prior to use. If used in liquid formthe compositions of this invention are preferably incorporated into abuffered, isotonic, aqueous solution. Examples of suitable diluents arenormal isotonic saline solution, standard 5% dextrose in water andbuffered sodium or ammonium acetate solution. Such liquid formulationsare suitable for parenteral administration, but may also be used fororal administration. It may be desirable to add excipients such aspolyvinylpyrrolidinone, gelatin, hydroxycellulose, acacia, polyethyleneglycol, mannitol, sodium chloride, sodium citrate or any other excipientknown to one of skill in the art to pharmaceutical compositionsincluding compounds of this invention. Alternatively, the pharmaceuticalcompounds may be encapsulated, tableted or prepared in an emulsion orsyrup for oral administration. Pharmaceutically acceptable solid orliquid carriers may be added to enhance or stabilize the composition, orto facilitate preparation of the composition. Liquid carriers includesyrup, peanut oil, olive oil, glycerin, saline, alcohols and water.Solid carriers include starch, lactose, calcium sulfate, dihydrate,teffa alba, magnesium stearate or stearic acid, talc, pectin, acacia,agar or gelatin. The carrier may also include a sustained releasematerial such as glycerol monostearate or glycerol distearate, alone orwith a wax. The amount of solid carrier varies but, preferably, will bebetween about 20 mg to about 1 gram per dosage unit. The pharmaceuticaldosages are made using conventional techniques such as milling, mixing,granulation, and compressing, when necessary, for tablet forms; ormilling, mixing and filling for hard gelatin capsule forms. When aliquid carrier is used, the preparation will be in the form of a syrup,elixir, emulsion or an aqueous or non-aqueous suspension. Such a liquidformulation may be administered directly or filled into a soft gelatincapsule.

The Examples which follow serve to illustrate this invention. TheExamples are not intended to limit the scope of this invention, but areprovided to show how to make and use the compounds of this invention.

EXAMPLE 1

Intermediate—(4-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(1R,2R,5R)-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl)methan-1-ol(4)

To a solution of compound 3 (2.0 g, 6.0 mmol) and 2,2-dimethoxypropane(1.2 g, 11.8 mmol) in dimethylformamide (20 mL) was addedp-toluenesulfonic acid (50 mg. 0.26 mmol) at 70° C. After 48 h at 70°C., the reaction was concentrated in vacuo to afford a solid. The solidwas dissolved in methanol (3 mL), then triturated with ethyl ether (50mL). The resultant crystals were collected by vacuum filtration toafford the intermediate 4.

To a solution of 4 (190 mg, 0.5 mmol) in anhydrous pyridine (5 mL), wasadded MsCl (80 microL, 1 mmol) at 0° C. The reaction mixture was stirredat the same temperature for 2 h. Pyridine was removed under reducedpressure, residue was taken in dichloromethane (50 mL), washed withwater (3×20 mL) and dried (Na₂SO₄). Evaporation of the solvent gaveproduct 5 as a white foam: ¹H NMR (CDCl₃) δ1.4 (s,3H), 1.6(s, 3H),2.0-2.2(m, 1H), 2.3-2.5(m, 1H), 2.9(s, 3H), 3.7-4.2(m, 4H), 4.4-4.6(m,3H), 4.8-5.0(bs, 1H), 5.1-5.2(bs, 1H), 5.4-5.5(bs, 1H), 6.1 (s, 1H),6.4-6.6(bs, 1H), 8.1 (s, 1H), 8.4(s, 1H)

A mixture of mesylate 5 (150 mg) and methanethiolate (150 mg) inacetonitrile (2 mL) and water (1 mL) was heated at 70 C for 24 h. Thesolvent was evaporated under reduced pressure and the residue waspurified by preparative TLC [methanol-dichloromethane (1:19)] to affordproduct 6: ¹H NMR (CDCl₃) δ 1.35 (s, 3H), 1.60 (s, 3H), 1.90-2.05 (m,1H), 2.05 (s, 3H), 2.30-2.40 (m, 1H), 2.70 (doublet of AB quartet, 2H),3.75-3.90 (m, 2H), 3.95-4.00 (m, 2H), 4.3-4.4 (m, 1H), 4.8-4.95 (m, 1H),5.00-5.05 (m, 1H), 5.45-5.50 (d, 1H), 6.00-6.10 (m, 2H), 7.85 (s, 1H),8.3 (s, 1H).

2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-(methylthiomethyl)oxolane-3,4-diol(7)

Compound 6 (50 mg) was dissolved in a mixture of acetic acid (8 mL) andwater (2 mL) and heated at 90° C. for 16 h. Solvents were removed underreduced pressure, and the residue was purified by preparative TLC[methanol-dichloromethane (1:9)] to afford compound 7: 1H NMR (CDCl₃) δ1.90-2.05 (m, 1H), 2.15 (s, 3H), 2.30-2.40 (in, 1H), 2.75-2.85 (m, 2H),3.80-3.90 (m, 2H), 3.90-4.00 (m, 2H), 4.30-4.45 (m, 2H), 4.50-4.55 (m,1H), 4.75-4.95 (m, 1H), 5.90-5.95 (m, 1H). 6.30-6.60 (m, 1H), 7.95 (s,1H), 8.25 (s, 1H).

2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(Ethylthio)methyl]oxolane-3,4-diol(8)

Compound 8 was prepared in the manner similar to that of 7 substitutingethane thiolate for methane thiolate. (M+1) 382.30

2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(Methylethylthio)methyl]oxolane-3,4-diol(10)

Compound 10 was prepared in the manner similar to that of 7 substitutingi-propane thiolate for methane thiolate. ¹H NMR (CDCl₃) δ 1.25 (d, 6H),1.90-2.05 (m, 1H), 2.15 (s. 3H), 2.30-2.40 (m, 1H), 2.85-2.87 (d, 2H),2.95 (septet, 1H), 3.80-3.90 (m, 2H), 3.95-4.05 (m, 2H), 4.35-4.40 (m,2H), 4.50-4.55 (m, 1H), 4.75-4.85 (m, 1H), 5.90-5.95 (d, 1H), 6.85-6.95(m, 1H), 7.95 (s, 1H), 8.25 (s, 1H).

2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-(phenylthiomethyl)oxolane-3,4-diol(11)

Compound 11 was prepared in the manner similar to that of 7 substitutingphenyl thiolate for methane thiolate. ¹H NMR (CDCl₃) 1.95-2.05 (m, 1H),2.30-2.40 (m, 1H), 3.2 (d, 2H), 3.80-3.90 (m, 2H), 3.95-4.10 (m, 2H),4.35-4.40 (d, 1H), 4.45 (t, 1H), 4.50-4.55 (m, 1H), 4.80-4.90 (m, 1H),5.85 (d, 1H), 6.70-6.80 (m, 1H), 7.15-7.30 (m, 3H), 7.35 (d, 2H), 7.75(s, 1H), 8.25 (s, 1H).

2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(4-Methoxyphenylthio)methyl]oxolane-3,4-diol(12)

This compound was prepared in the manner similar to that of 7substituting 4-methoxyphenyl thiolate for methane thiolate. (M+1)=460.4

2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(4-chlorophenylthio)methyl]oxolane-3,4-diol(13)

This compound was prepared in a manner similar to that of 7 substituting4-chlorophenyl thiolate for methane thiolate. (M+1)=464.3

2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(4-fluorophenylthio)methyl]oxolane-3,4-diol(14)

This compound was prepared in a manner similar to that of 7 substituting4-fluorophenyl thiolate for methane thiolate. (M+1)=448.3

2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(4-methylphenylthio)methyl]oxolane-3,4-diol(15)

This compound was prepared in a manner similar to that of 7 substituting4-methylphenyl thiolate for methane thiolate. (M+1)=444.38

2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(4-(trifluoromethyl)phenylthio)methyl]oxolane-3,4-diol(16)

This compound was prepared in a manner similar to that of 7 substituting4-trifluoromethylphenyl thiolate for methane thiolate. (M+1)=488.36

2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(2-Methoxyphenylthio)methyl]oxolane-3,4-diol(17)

This compound was prepared in a manner similar to that of 7 substituting2-methoxyphenyl thiolate for methane thiolate. (M+1)=460.4

(5-{6-[((3R)oxolan-3-yl)amino]purinyl-9-yl}(2S,3S,4R,5R)-3,4-dihydroxyoxolan-2-yl)(ethylsulfonyl)methane(9)

To a cooled solution of sulfide 8 in methanol at 0° C. under nitrogenwas added 3 eq. of Oxone (Potassium peroxy monosulfate) and the reactionmixture was allowed to stir at the same temperature for 1 hour. Afterthe starting material consumed (by TLC), the reaction mixture wasconcentrated and filtered through a small plug of silica gel.Purification by preparative TLC [methanol-dichloromethane (1:19)]afforded 9 as an off-white hygroscopic solid. (M+1)=414.28

2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(2,4-difluorophenylthio)methyl]oxolane-3,4-diol(18)

This compound was prepared in a manner similar to that of 7 substituting2,4-difluorophenyl thiolate for methane thiolate. (M+1)=466.23

2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(2,6-dichlorophenylthio)methyl]oxolane-3,4-diol(19)

This compound was prepared in a manner similar to that of 7 substituting2,6-dichlorophenyl thiolate for methane thiolate. (M+1)=498.18

2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(3-fluorophenylthio)methyl]oxolane-3,4-diol(20)

This compound was prepared in a manner similar to that of 7 substituting3-fluorophenyl thiolate for methane thiolate. (M+1)=448.26

2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(2-fluorophenylthio)methyl]oxolane-3,4-diol(21)

This compound was prepared in a manner similar to that of 7 substituting2-fluorophenyl thiolate for methane thiolate. (M+1)=448.24

5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(2S,3R,4R,5R)-4-acetyloxy-2-[(fluorophenylthio)methyl]oxolan-3-ylacetate (22)

To a solution of compound 21 (139 mg) in pyridine (2 mL) at 23° C. wasadded acetic anhydride (0.1 mL). After 3 h at 23° C., the reaction wasconcentrated in vacuo. The residue was dissolved in methylene chloride(50 mL), washed with water (3×10 mL), and dried (Na₂SO₄). Afterconcentration in vacuo, the residue was purified by flash chromatography(methylene chloride:methanol 20:1 followed by 9:1) to afford compound 22(170 mg):

Methyl 2[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(2S,3S,4R,5R)-3,4-dihydroxyoxolan-2-yl)methylthio]benzoate(23)

To a solution of Compound 4 (0.377 g, 1 mmol) in 5 mL of THF, was addedTriphenylphosphine (0.524 g, 2 mmol), DEAD (0.40 mL. 2 mmoles), let stirfor 5 minutes before adding 2-carbomethoxythiophenol (0.5 mL). Reactionwas allowed to stir under reflux. After 72 h of reflux, the reaction wasconcentrated in vacuo and the residue purified by flash columnchromatography (20% EtOAc/Hexanes) to give a clear viscous oil. It wastaken into a mixture of acetic acid (8 mL) and water (2 mL) and heatedat 80 C for 16 h. Solvents were removed in vacuo and the residue waspurified by prep TLC [methanol-dichloromethane (1:9)] to give compound23. (M+1)=488.5

{2[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(2S,3S,4R,5R)-3,4-dihydroxyoxolan-2-yl)methylthio]phenyl}-N-methylcarboxamidebenzoate(24)

Compound 23 was taken into 40% aq.methylamine (2 mL) and I-propanol (2mL) and heated at 70 C for 16 h. Solvents were removed in vacuo and theresidue was purified by prep TLC TLC [methanol-dichloromethane (1:9)] togive compound 24. (M+1)=487.5

2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-(benzoxazol-2-ylthiomethyl)oxolane-3,4-diol(25)

This compound was prepared in a manner similar to that of 23substituting 2-mercaptobenzoxazole for 2-carbmethoxy thiophenol(M−1)=471.4

2-{6-[((3S)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(1-methylimidazol-2-yl-thio)methyl]oxolane-3,4-diol(26)

Compound 26-was prepared in the manner of compound 23 substituting2-mercapto-1-methylimidazole for 2-carbomethoxythiophenol [MS 434.4(M+1)].

2-{6-[((3S)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-(pyrimidine-2-ylthiomethyl)oxolane-3,4-diol(27)

Compound 27 was prepared in the manner of compound 23 substituting2-mercaptopyrimidine for 2-carbonlcthoxythiophenol [MS 432.4 (M−1)].

2-{6-[((3S)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-(2-pyridylthiomethyl)oxolane-3,4-diol(28)

Compound 28 was prepared in the manner of compound 23 substituting2-mercaptopyridine for 2-carbomethoxythiophenol [MS 431.4 (M+1)].

2-{6-[((3S)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-(4-pyridylthiomethyl)oxolane-3,4-diol(29)

Compound 29 was prepared in the manner of compound 23 substituting4-mercaptopyridine for 2-carbomethoxythiophenol [MS 431.4 (M+1)].

5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(2S,3R,4R,5R)₄-acetyloxy-2-[(4-fluorophenylthio)methyl]oxolan-3-yl]acetate(30) (M+1)=532.17. EXAMPLE 2

Binding Assays—DDT₁ Cells

Cell Culture

DDT cells (hamster vas deferens smooth muscle cell line) were grown asmonolayers in petri dishes using Dulbecco's Modified Eagle's Medium(DMEM) containing 2.5 g ml⁻¹ amphotericin B, 100 U ml⁻¹ penicillin G,0.1 mg ml⁻¹ streptomycin sulfate and 5% fetal bovine serum in ahumidified atmosphere of 95% air and 5% CO₂. Cells were subculturedtwice weekly by dispersion in Hank's Balanced Salt Solution (HBSS)without the divalent cations and containing 1 mM EDTA. The cells werethen seeded in growth medium at a density of 1.2×10⁵ cells per plate andexperiments were performed 4 days later at approximately one daypreconfluence.

Membrane Preparations

Attached cells were washed twice with HBSS (2×10 ml), scraped free ofthe plate with the aid of a rubber policeman in 5 ml of 50 mM Tris-HClbuffer pH 7.4 at 4° C. and the suspension homogenized for 10 s. Thesuspension was then centrifuged at 27,000×g for 10 min. The pellet wasresuspended in homogenization buffer by vortexing and centrifuged asdescribed above. The final pellet was resuspended in 1 vol of 50 mMTris-HCl buffer pH 7.4 containing 5 mM MgCl₂ for A₁ AdoR assays. For the[³⁵S]GTPγS binding assay the final pellet was resuspended in 50 mMTris-HCl pH 7.4 containing 5 mM MgCl₂, 100 mM NaCl and 1 mMdithiothreitol. This membrane suspension was then placed in liquidnitrogen for 10 min, thawed and used for assays. The protein content wasdetermined with a Bradford™ Assay Kit using bovine serum albumin asstandard.

Competitive Binding Assay

Pig striatum were prepared by homogenation in 50 mM Tris buffer (5×volume of tissue mass pH=7.4). After centrifugation at 19,000 rpm for 25minutes at 4° C., the supernatant was discarded, and the process wasrepeated twice. Compositions of this invention were assayed to determinetheir affinity for the A₁ receptor in a pig striatum membrane prep or aDDT₁ membrane prep. Briefly, 0.2 mg of pig striatal membranes or DDT₁cell membranes were treated with adenosine deaminase and 50 mM Trisbuffer (pH=7.4) followed by mixing. To the pig membranes was added 2 μLof serially diluted DMSO stock solution of the compounds of thisinvention at concentrations ranging from 100 microM to 10 nM. Thecontrol received 2 microL of DMSO alone, then the antagonist [³H]8-cyclopentylxanthine (CPX) for pig striatum or the agonist [³H]2-chloro-6-cyclopentyladenosine (CCPA) for DDT₁ membranes in Tris buffer(50 mM, pH of 7.4) was added to achieve a final concentration of 2 nM.After incubation at 23 C for 2 h, then the solutions were filtered usinga membrane harvester using multiple washing of the membranes (3×). Thefilter disks were counted in scintillation cocktail affording the amountof displacement of tritiated CPX or by the competitive bindingcompositions of this invention. Greater than a 5 point curve was used togenerate Ki's and the number of experiments is indicated in the columnmarked in Table 1, below: TABLE 1 Compound # K_(i) - DDT₁ cell membraneK_(i) - Pig Striatum 7 — 222 nM 10 — 188 nM 11 —  44 nM 12  820 nM — 14 363 nM — 15  922 nM — 16 7701 nM — 17  947 nM —

EXAMPLE 3

[³⁵S]GTPγS Binding Assays

A₁-agonist stimulated [³⁵S] GTPγS binding was determined by amodification of the method described by Giersckik et al. (1991) andLorenzen et al. (1993). Membrane protein (30-50 μg) was incubated in avolume of 0.1 ml containing 50 mM Tris-HCl buffer pH 7.4, 5 mM MgCl₂,100 mM NaCl, 1 mM dithiothreitol, 0.2 units ml⁻¹ adenosine deaminase,0.5% BSA, 1 mM EDTA, 10 mM GDP, 0.3 nM [³⁵S]GTPγS and with or withoutvarying concentrations of CPA for 90 min at 30° C. Nonspecific bindingwas determined by the addition of 10 μM GTPγS. Agonist stimulatedbinding was determined as the difference between total binding in thepresence of CPA and basal binding determined in the absence of CPA.Previous reports have shown that agonist stimulated [³⁵S]GTPγS bindingwas dependent on the presence of GDP (Gierschik et al., 1991; Lorenzenet al., 1993; Traynor & Nahorski, 1995). In preliminary experiments, itwas found that 10 μM GDP gave the optimal stimulation of CPA dependent[³⁵S]GTPγS binding and this concentration was therefore used in allstudies. In saturation experiments, 0.5 nM [³⁵S]GTPγS was incubated with0.5-1000 nM GTPγS. At the end of the incubation, each suspension wasfiltered and the retained radioactivity determined as described above.Result are presented normalized to the full agonistN-6-cyclopentyladenosine, CPA. TABLE 2 Compound # GTP□S CPA 100%  8 104%12 52% 13 69% 14 61% 15 48% 16 31% 17 52%

EXAMPLE 4

cAMP Assay

A scintillation proximity assay (SPA) using rabbit antibodies directedat cAMP using an added tracer of adenosine 3′,5′-cyclic phosphoric acid2′-O-succinyl-3-[¹²⁵I]iodotyrosine methyl ester and fluoromicrospherescontaining anti-rabbit specific antibodies as described by AmershamPharmacia Biotech (Biotrak cellular communication assays). Briefly, DDT₁cells were cultured in clear bottomed 96 well microtiter plates withopaque wells at concentrations between 10⁴ to 10⁶ cells per well in 40μl of HBSS at 37° C. (5% CO₂ and 95% humidity). The partial or full A₁agonists (5 μl) of this invention were incubated at variousconcentrations with the DDT₁ cells in the presence of rolipram (50 μM),and 5 μM forskolin for 10 min at 37° C. The cells were immediately lysedby treatment 5 μl of 10% dodecyltrimethylammonium bromide followed byshaking using microplate shaker. After incubation of the plate for 5minutes, an immunoreagent solution (150 μl containing equal volumes oftracer, antiserum, and SPA fluorospheres) was added to each wellfollowed by sealing the plate. After 15-20 h at 23° C., the amount ofbound [¹²⁵I] cAMP to the fluoromicrospheres was determined by countingin a microtitre plate scintillation counter for 2 minutes. Comparison ofcounts with standard curves generated for cAMP using a similar protocolafforded the cAMP present after cell lysis. Results are presentednormalized to the full agonist N-6-cyclopentyladenosine, CPA. Thus, thefull agonist CPA diminished the amount of forskolin induced cAMPgeneration back to basal levels. TABLE 3 Compound # Camp CPA 107%  8 37%12 −9% 13 30% 14 47% 15 22% 16 22% 17 18%

1. A composition of matter having the formula:

wherein X¹═S, S(O), S(O)₂; R¹ is a monocyclic or polycyclic heterocyclicgroup containing from 3 to 15 carbon atoms wherein at least one carbonatom is substituted p ith an atom or molecule selected from the groupconsisting of N, O, P and S—(O)₀₋₂ wherein R₁ does not contain anepoxide group; R₂ is selected from the group consisting of hydrogen,halo, CF₃, and cyano; R₃ and R₄ are each independently selected from thegroup consisting of hydrogen, —(CO)—R′, and —(CO)—R″ wherein R′ and R″are each independently selected from the group consisting of C₁₋₁₅alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl, heterocyclyl, aryl, and heteroaryl,which alkyl, alkenyl, alkynyl, aryl, heterocyclyl, and heteroaryl areoptionally substituted with from 1 to 3 substituents independentlyselected from the group of halo, NO₂, heterocyclyl, aryl, heteroaryl,CF₃, CN, OR²⁰, SR²⁰, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, SO₂NR²⁰COR²²,SO₂NR²⁰CO₂R²², SO₂NR²⁰CON(R²⁰)₂, N(R²⁰)₂, NR²⁰COR²², NR²⁰CO₂R²²,NR²⁰CON(R²⁰)₂, NR²⁰C(NR²⁰)NHR²³, COR²⁰, CO₂R²⁰, CON(R²⁰)₂, CONR²⁰SO₂R²²,NR²⁰SO₂R²², SO₂NR²⁰CO₂R²², OCONR²⁰SO₂R²², OC(O)R²⁰, C(O)OCH₂OC(O)R²⁰,and OCON(R²⁰)₂ and wherein each optional heteroaryl, aryl, andheterocyclyl substituent is further optionally substituted with halo,NO₂, alkyl, CF₃, amino, mono- or di-alkylamino, alkyl or aryl orheteroaryl amide, NR²⁰COR²², NR²⁰SO₂R²², COR²⁰, CO₂R²⁰, CON(R²⁰)₂,NR²⁰CON(R²⁰)₂, OC(O)R²⁰, OC(O)N(R²⁰)₂, SR²⁰, S(O)R²², SO₂R²²,SO₂N(R²⁰)₂, CN, or OR²⁰; R₅ is selected from the group consisting ofC₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl, heterocyclyl, aryl, andheteroaryl, wherein each alkyl, alkenyl alkynyl, aryl, heterocyclyl, andheteroaryl are optionally substituted with from 1 to 3 substituentsindependently selected from the group consisting of halo, alkyl, NO₂,heterocyclyl, aryl, heteroaryl, CF₃, CN, OR²⁰, SR²⁰, S(O)₃R²⁰, S(O)R²²,SO₂R²², SO₂N(R²⁰)₂, SO₂NR²⁰COR²², SO₂NR²⁰CO₂R²², SO₂NR²⁰CON(R²⁰)₂,P(O)(OR²⁰)₂, N(R²⁰)₂, NR²⁰COR²², NR²⁰CO₂R²², NR²⁰CON(R²⁰)₂,NR²⁰C(NR²⁰)NHR²³, COR²⁰, CO₂R²⁰, CON(R²⁰)₂, CONR²⁰SO₂R²², NR²⁰SO₂R²²,SO₂NR²⁰CO₂R²², OCONR²⁰SO₂R²², OC(O)R²⁰, C(O)OCH₂OC(O)R²⁰, and OCON(R²⁰)₂and wherein the optional heteroaryl, aryl, and heterocyclyl substituentare each further optionally substituted x-ith halo, NO₂, alkyl, CF₃,amino, mono- or di-alkylamino, alkyl or aryl or heteroaryl amide,NR²⁰COR²², NR²⁰SO₂R²², COR²⁰, CO₂R²⁰, CON(R²⁰)₂, NR²⁰CON(R²⁰)₂,OC(O)R²⁰, OC(O)N(R²⁰)₂, SR²⁰, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, CN, or OR²⁰;R²⁰ is selected from the group consisting of H, C₁₋₁₅ alkyl, C₂₋₁₅alkenyl, C₂₋₁₅ alkynyl, heterocyclyl, aryl, and heteroaryl, which alkyl,alkenyl, alkynyl, heterocyclyl, aryl, and heteroaryl are optionallysubstituted with from 1 to 3 substituents independently selected fromhalo, alkyl, mono- or dialkylamino, alkyl or aryl or heteroaryl amide,CN, O—C₁₋₆ alkyl, CF₃, aryl, and heteroaryl: and R²² is selected fromthe group consisting of C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, C₂₋₁₅ alkynyl,heterocyclyl, aryl, and heteroaryl, which alkyl, alkenyl, alkynyl,heterocyclyl, aryl, and heteroaryl are optionally substituted with from1 to 3 substituents independently selected from halo, alkyl, mono- ordialkylamino, alkyl or aryl or heteroaryl amide, CN, O—C₁₋₆ alkyl, CF₃,and heteroaryl.
 2. The composition of claim 1 wherein R₂ is selectedfrom the group consisting of hydrogen, and halo; R₃ and R₄ are eachindependently selected from the group consisting of hydrogen, —(CO)—R′,and —(CO)—R″ wherein R′ and R″ are each independently selected from thegroup consisting of C₁₋₁₅ alkyl, heterocyclyl, aryl, and heteroaryl,which alkyl, aryl, heterocyclyl, and heteroaryl are each optionallysubstituted with from 1 to 2 substituents independently selected fromthe group of halo, NO₂, heterocyclyl, aryl, heteroaryl, CF₃, CN, OR²⁰,S(O)R²², SO₂R²², SO₂N(R²⁰)₂, N(R²⁰)₂, NR²⁰COR²², NR²⁰CO₂R²²,NR²⁰CON(R²⁰)₂. NR²⁰C(NR²⁰)NHR²⁰, COR²⁰, CO₂R²⁰, CON(R²⁰)₂, CONR²⁰SO₂R²²,NR²⁰SO₂R²² and wherein each optional heteroaryl, aryl, and heterocyclylsubstituent is further optionally substituted with halo, NO₂, alkyl,CF₃, amino, mono- or di-alkylamino, CN, or OR²⁰; R₅ is selected from thegroup consisting of C₁₋₁₅ alkyl, C₁₋₁₅ alkenyl, C₂₋₁₅ alkynyl,heterocyclyl, aryl, and heteroaryl, wherein alkyl, alkenyl, alkynyl,aryl, heterocyclyl, and heteroaryl are optionally substituted with from1 to 3 substituents independently selected from the group of halo,alkyl, heterocyclyl, aryl, heteroaryl, CF₃, CN, OR²⁰, SR²⁰, N(R²⁰)₂,S(O)R²², S(O)₃R²⁰, SO₂R²², SO₂N(R²⁰)₂, NR²⁰CO₂R²², NR²⁰CON(R²⁰)₂, COR²⁰,CO₂R²⁰, CON(R²⁰)₂, and wherein each optional heteroaryl, and arylsubstituent is optionally substituted with halo, alkyl, CF₃, CO₂R²⁰,CON(R²⁰)₂, NR²⁰CON(R²⁰)₂, SR²⁰, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, CN, orOR²⁰; R²⁰ is selected from the group consisting of H, C₁₋₁₅ alkyl, aryl,and heteroaryl, which alkyl, aryl, and heteroaryl are each optionallysubstituted with from 1 to 2 substituents independently selected fromhalo, alkyl, mono- or dialkylamino, CN, O—C₁₋₆ alkyl, CF₃; and R²² isselected from the group consisting of C₁₋₁₅ alkyl, aryl, and heteroaryl,which alkyl, aryl, and heteroaryl are each optionally substituted withfrom 1 to 2 substituents independently selected from halo, alkyl, mono-or dialkylamino, alkyl or CN, O—C₁₋₆ alkyl, and CF₃.
 3. The compositionof claim 1 wherein R₂ is a hydrogen: R₃ and R₄ are each independentlyselected from the group consisting of hydrogen, —(CO)—R′ and —(CO)—R″wherein R′ and R″ are each independently selected from the groupconsisting of C₁₋₁₀ alkyl, aryl, and heteroaryl, which alkyl, aryl, andheteroaryl are optionally substituted with from 1 to 2 substituentsindependently selected from the group of halo, NO₂, aryl, heteroaryl,CF₃, CN, OR²⁰, N(R²⁰)₂, S(O)R²², SO₂R²², NR²⁰COR²², COR²⁰, CO₂R²⁰,CON(R²⁰)₂, NR²⁰SO₂R²², and wherein each optional heteroaryl, aryl, andheterocyclyl substituent is further optionally substituted with halo,NO₂, alkyl, CF₃; R₅ is selected from the group consisting of C₁₋₁₅,alkyl. C₂₋₁₅ alkenyl, heterocyclyl, aryl, and heteroaryl, wherein eachalkyl, alkenyl, aryl, heterocyclyl, and heteroaryl are optionallysubstituted with from 1 to 3 substituents independently selected fromthe group consisting of hallo, alkyl, aryl, heteroaryl, CF₃, CN, OR²⁰,SR²⁰, N(R²⁰)₂, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, NR²⁰CO₂R²², NR²⁰CON(R²⁰)₂,COR²⁰, CO₂R²⁰, CON(R²⁰)₂, and wherein each optional heteroaryl, and arylsubstituent is further optionally substituted with halo, alkyl, CF₃,CO₂R²¹, CON(R²⁰)₂, NR²¹CON(R²⁰)₂, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, CN, andOR²⁰; R²⁰ is selected from the group consisting of H, C₁₋₆ alkyl, andaryl, which alkyl, and aryl, are optionally substituted with 1substituent selected from halo, alkyl, mono- or dialkylamino, CN, O—C₁₋₆alkyl, CF₃; and R²² is selected from the group consisting of C₁₋₆ alkyland aryl, which alkyl and aryl are optionally substituted with 1substituent independently selected from halo, alkyl, mono- ordialkylamino, alkyl or CN, O—C₁₋₆ alkyl, and CF₃.
 4. The composition ofclaim 1 wherein R₂ is a hydrogen: R₃ and R₄ are each independentlyselected from the group consisting of hydrogen, —(CO)—R′ and —(CO)—R″wherein R′ and R″ are each independently selected from the groupconsisting of C₁₋₆ alkyl, and aryl, which alkyl and aryl are optionallysubstituted with from 1 to 2 substituents independently selected fromthe group of halo, NO₂, aryl, CF₃, CN, OR²⁰, N(R²⁰)₂, S(O)R²², SO₂R²²,N(R²⁰)₂, and wherein each optional aryl substituent is optionallysubstituted with halo, NO₂, alkyl, CF₃; R₅ is selected from the groupconsisting of C₁₋₁₅ alkyl, C₂₋₁₅ alkenyl, aryl, and heteroaryl, whereinalkyl, alkenyl, aryl, and heteroaryl are optionally substituted withfrom 1 to 3 substituents independently selected from the groupconsisting of halo, alkyl, aryl, heteroaryl, CF₃, CN, OR²⁰, SR²⁰,N(R²⁰)₂, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, NR²⁰CO₂R²², NR²⁰CON(R²⁰)₂, CO₂R²⁰,CON(R²⁰)₂, and wherein each optional heteroaryl, and aryl substituent isfurther optionally substituted with halo, alkyl, CF₃, CO₂R²⁰, CON(R²⁰)₂,S(O)R²², SO₂R²², SO₂N(R²⁰)₂, CN, or OR²⁰; R²⁰ is selected from the groupconsisting of H, C₁₋₆ alkyl, and aryl, which alkyl and aryl areoptionally substituted with 1 substituent selected from halo, alkyl,mono- or dialkylamino, CN, O—C₁₋₆ alkyl, CF₃; and R²² is selected fromthe group consisting of C₁₋₆ alkyl and aryl, which alkyl and aryl areoptionally substituted with 1 substituent selected from halo, alkyl orCN, O—C₁₋₆ alkyl, and CF₃.
 5. The composition of claim 1 wherein R₂ is ahydrogen: R₃ and R₄ are each independently selected from the groupconsisting of hydrogen, —(CO)—R′ and —(CO)—R″ wherein each R′ and R″ areindependently selected from the group consisting of C₁₋₆ (alkyl whichalkyl are optionally substituted with 1 substituent selected from thegroup of aryl, CF₃, CN, OR²⁰, N(R²⁰)₂, and wherein each optional arylsubstituent is further optionally substituted with halo, NO₂, alkyl,CF₃; R₅ is selected from the group consisting of C₁₋₈ alkyl, C₂₋₈alkenyl, and aryl wherein alkyl, alkenyl, and aryl are optionallysubstituted with from 1 to 2 substituents independently selected fromthe group consisting of halo, alkyl, aryl, heteroaryl, CF₃, CN, OR²⁰,S(O)R²², SO₂R²², SO₂N(R²⁰)₂. NR²⁰CON(R²⁰)₂, CO₂R²⁰, CON(R²⁰)₂, andwherein each optional heteroaryl, and aryl substituent is furtheroptionally substituted with halo, alkyl, CF₃, CO₂R²⁰, CN, and OR²⁰; R²⁰is selected from the group consisting of H C₁₋₆ alkyl; and R²² isselected from the group consisting of C₁₋₆.
 6. The composition of claim1 wherein X¹═S or SO₂; R₂ is a hydrogen; R₃ and R₄ are eachindependently selected from the group consisting of hydrogen, —(CO)—R′and —(CO)—R″ wherein R′ and R″ are each independently selected from thegroup consisting of C₁₋₆ alkyl; R₅ is selected from the group consistingof C₁₋₈ alkyl, and aryl wherein alkyl, and aryl are optionallysubstituted with from 1 to 2 substituents independently selected fromthe group consisting of halo, alkyl, aryl, heteroaryl, CF₃, CN, OR²⁰,S(O)R²², SO₂R²², SO₂N(R²⁰)₂, NR²⁰CON(R²⁰)₂, CO₂R²⁰, CON(R²⁰)₂, andwherein each optional heteroaryl, and aryl substituent is furtheroptionally substituted with halo, alkyl, CF₃, CO₂R²⁰, CN, and OR²⁰; R²⁰is selected from the group consisting of H, C₁₋₆ alkyl; and R²² isselected from the group consisting of C₁₋₆.
 7. The composition of claim1 wherein X¹═S or SO₂; R₂ is a hydrogen; R₃ and R₄ are hydrogen; R₅ isselected from the group consisting of C₁₋₈ alkyl, and aryl whereinalkyl, and aryl are optionally substituted with from 1 to 2 substituentsindependently selected from the group consisting of halo, alkyl, CF₃,CN, OR²⁰, CO₂R²⁰; and R²⁰ is selected from the group consisting of H,C₁₋₆ alkyl.
 8. The composition of claim 1 wherein X¹═S or SO₂: R₂ is ahydrogen; R₃ and R₄ are hydrogen; R₅ is selected from the groupconsisting of C₁₋₈ alkyl, and aryl wherein alkyl, and aryl areoptionally substituted with from 1 to 2 substituents independentlyselected from the group consisting of halo, alkyl, CF₃, OR²⁰; and R²⁰ isselected from the group consisting of H, C₁₋₆ alkyl.
 9. The compositionof claim 1 wherein X¹═S or SO₂; R₂ is a hydrogen; R₃ and R⁴ areindependently selected from the group consisting of hydrogen, —(CO)—R′and —(CO)—R″ wherein R′ and R″ are each independently selected from thegroup consisting of C₁₋₆ alkyl which alkyl are optionally substitutedwith 1 substituent selected from the group consisting of aryl, CF₃, CN,OR²⁰, N(R²⁰)₂, and wherein each optional aryl substituent is furtheroptionally substituted with halo, NO₂, alkyl, CF₃; R₅ is C₁₋₈ alkyl,wherein alkyl, is optionally substituted with from 1 to 2 substituentsindependently selected from the group consisting of halo, alkyl, aryl,heteroaryl, CF₃, CN, OR²⁰, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, NR²⁰CON(R²⁰)₂,CO₂R²⁰, CON(R²⁰)₂, wherein each optional heteroaryl, and arylsubstituent is further optionally substituted with halo, alkyl, CF₃,CO₂R²⁰, CN, and OR²⁰; R²⁰ is selected from the group consisting of H,C₁₋₆ alkyl; and R²² is selected from the group consisting of C₁₋₆. 10.The composition of claim 1 wherein X¹═S or SO₂; R₂ is a hydrogen; R₃ andR₄ are independently selected from the group consisting of hydrogen,—(CO)—R′ and —(CO)—R″ wherein R′ and R″ are each independently selectedfrom the group consisting of C₁₋₆ alkyl: R₅ is C₁₋₈ alkyl that isoptionally substituted with from 1 to 2 substituents independentlyselected from the group consisting of aryl, heteroaryl, OR²⁰, S(O)R²²,CO₂R²⁰, CON(R²⁰)₂, and wherein each optional heteroaryl, and arylsubstituent is further optionally substituted with halo, alkyl, CF₃,COR²R²⁰, CN, and OR²⁰; R²⁰ is selected from the group consisting of H,C₁₋₆ alkyl; and R²² is selected from the group consisting of C₁₋₆. 11.The composition of claim 1 wherein ═S or SO₂: R₂ is a hydrogen; R₃ andR₄ are hydrogen; R₅ is C₁₋₈ alkyl that is optionally substituted with 1substituent selected from the group consisting of CO₂R²⁰, and CON(R²⁰)₂;and R²⁰ is selected from the group consisting of H, and methyl.
 12. Thecomposition of claim 11 wherein R₅ is C₁₋₆ alkyl.
 13. The composition ofclaim 1 wherein R₅ is selected from the group consisting of methyl andethyl and isopropyl.
 14. The composition of claim 1 wherein R₂ is ahydrogen; R₃ and R₄ are each independently selected from the groupconsisting of hydrogen, —(CO)—R′ and —(CO)—R″ wherein each R′ and R″ areindependently selected from the group consisting of C₁₋₆ alkyl, andaryl, which alkyl and aryl are optionally substituted with from 1 to 2substituents independently selected from the group of halo, NO₂, aryl.CF₃, CN, OR²⁰, N(R²⁰)₂, S(O)R²², SO₂R²², N(R²⁰)₂, and wherein eachoptional aryl substituent is further optionally substituted with halo,NO₂, alkyl, CF₃; R₅ is selected from the group consisting of, aryl, andheteroaryl, wherein aryl, and heteroaryl are optionally substituted withfrom 1 to 3 substituents independently selected from the groupconsisting of halo, alkyl, aryl, heteroaryl, CF₃, CN, OR²⁰, SR²⁰,N(R²⁰)₂, S(O)R²², SO₂R²², SO₂N(R²⁰)₂, NR²⁰CO₂R²², NR²⁰CON(R²⁰), CO₂R²⁰,CON(R²⁰)₂, and wherein each optional heteroaryl, and aryl substituent isfurther optionally substituted with halo, alkyl, CF₃, CO₂R²⁰, CON(R²⁰)₂,S(O)R²², SO₂R²², SO₂N(R²⁰)₂, CN, or OR²⁰; R²⁰ is selected from the groupconsisting of H, C₁₋₆ alkyl, and aryl, which alkyl and aryl areoptionally substituted with 1 substituent selected from halo, alkyl,mono- or dialkylamino, CN, O—C₁₋₆ alkyl, CF₃; and R²² is selected fromthe group consisting of C₁₋₆ alkyl and alkyl and aryl, which alkyl andaryl are optionally substituted with 1 substituent selected from halo,alkyl or CN, O—C₁₋₆ alkyl, and CF₃.
 15. The composition of claim 1wherein X¹═S; R₂ is a hydrogen; R₃ and R₄ are each independentlyselected from the group consisting of hydrogen, —(CO)—R′ and —(CO)—R″wherein R′ and R″ are each independently selected from the groupconsisting of C₁₋₆ alkyl; R₅ is selected from the group consisting of,aryl, and heteroaryl, wherein aryl, and heteroaryl are optionallysubstituted with from 1 to 3 substituents independently selected fromthe group consisting of halo, alkyl, CF₃, CN, OR²⁰, SR²⁰, CO₂R²⁰,CON(R²⁰)₂; and R²⁰ is selected from the group consisting of H, C₁₋₃alkyl.
 16. The composition of claim 1 wherein X¹═S; R₂ is a hydrogen; R₃and R₄ are hydrogen; R₅ is aryl that is optionally substituted with from1 to 2 substituents independently selected from the group consisting ofhalo, alkyl, CF₃, OR²⁰, CO₂R²⁰, CON(R²⁰); R²⁰ is selected from the groupconsisting of H, and methyl; and R²² is selected from the groupconsisting of C₁₋₆ alkyl.
 17. The composition of claim 16 wherein R₅ isphenyl that is optionally substituted with a substituent selected fromthe group consisting of methoxy, chloro, fluoro, methyl, andtrifluoromethyl.
 18. The composition of claim 1 wherein R¹ is mono orpolysubstituted with one or more compounds selected from the groupconsisting of halogen, oxo, hydroxyl, lower alkyl, substituted loweralkyl, alkoxy, aryl, acyl, aryloxy, carboxyl, substituted aryl,heterocycle, heteroaryl, substituted heteroaryl, cycloalkyl, substitutedcycloalkyl, nitro, cyano and mixtures thereof.
 19. The composition ofmatter of claim 1 wherein R¹ is a monocyclic, bicyclic, or tricycliccycloalkyl group containing from 3 to 15 carbon atoms wherein at leastone carbon atom is substituted with an atom or molecule selected fromthe group consisting of O or S—(O)₀₋₂.
 20. The composition of claim 19wherein R¹ is mono or polysubstituted with one or more compoundsselected from the group consisting of halogen, oxo, hydroxyl, loweralkyl, substituted lower alkyl, alkoxy, aryl, acyl, aryloxy, carboxyl,substituted aryl, heterocycle, heteroaryl, substituted heteroaryl,cycloalkyl, substituted cycloalkyl, nitro, cyano and mixtures thereof.21. The composition of claim 1 wherein R¹ is:

wherein R₁′, R₁″, R₁′″, and R₁″″ are each independently selected fromthe group halogen, hydroxyl, lower alkyl, substituted lower alkyl,alkoxy, aryl, acyl, aryloxy, carboxyl, substituted aryl, heterocycle,heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl,nitro, cyano and mixtures thereof and X is O, or S(—O)O₀₋₂.
 22. Thecomposition of claim 21 wherein R₁′″ and R₁″″ can together be a singleoxygen atom.
 23. The composition of claim 21 wherein R₁′, R₁″, R₁′″, andR₁″″ are each individually selected from the group H, lower alkyl,substitute lower alkyl, alkoxy, aryl, and substituted aryl.
 24. Thecomposition of claim 21 wherein R₁′, R₁″, R₁′″, and R₁″″ are eachindividually selected from the group H, lower alkyl, and substitutelower alkyl.
 25. The composition of claim 1 wherein R¹ is selected fromthe group consisting

wherein each R may be independently selected from the group consistingof H, lower alkyl, and substituted lower alkyl and wherein X is O, orS(—O)₀₋₂.
 26. The composition of claims 1 or 2 or 3 or 4 or 5 or 6 or 7or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 wherein R₁ isselected from the group consisting of 3-tetrahydrofuranyl,3-tetrahydrothiofuranyl, 4-pyranyl, and 4 thiopyranyl.
 27. Thecomposition of claims 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or11 or 12 or 13 or 14 or 15 or 16 wherein R₁ is 3-tetrahydrofuranyl. 28.The composition of claim 1 wherein the compound is selected from thegroup of compounds consisting of2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-(methylthiomethyl)oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(Ethylthio)methyl]oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(Methylethylthio)methyl]oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-(phenylthiomethyl)oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(4-Methoxyphenylthio)methyl]oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(4-chlorophenylthio)methyl]oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(4-fluorophenylthio)methyl]oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(4-methylphenylthio)methyl]oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(4-(trifluoromethyl)phenylthio)methyl]oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(2-Methoxyphenylthio)methyl]oxolane-3,4-diol;(5-{6-[((3R)oxolan-3-yl)amino]purinyl-9-yl}(2S,3S,4R,5R)-3,4-dihydroxyoxolan-2-yl)(ethylsulfonyl)methane2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(2,4-difluorophenylthio)methyl]oxolane-3,4-diol;2-{6-[((R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(2-fluorophenylthio)methyl]oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(3-fluorophenylthio)methyl]oxolane-3,4-diol;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(2-fluorophenylthio)methyl]oxolane-3,4-diol;5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(2S,3R,4R,5R)-4-acetyloxy-2-[(fluorophenylthio)methyl]oxolan-3-ylacetate; Methyl2[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(2S,3S,4R,5R)-3,4-dihydroxyoxolan-2-yl)methylthio]benzoate;{2[(5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(2S,3S,4R,5R)-3,4-dihydroxyoxolan-2-yl)methylthio]phenyl}-N-methylcarboxamidebenzoate;2-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-(benzoxazol-2-ylthiomethyl)oxolane-3,4-diol;2-{6-[((3S)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-[(1-methylimidazol-2-yl-thio)methyl]oxolane-3,4-diol;2-{6-[((3S)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-(pyrimidine-2-ylthiomethyl)oxolane-3,4-diol:2-{6-[((3S)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-(2-pyridylthiomethyl)oxolane-3,4-diol;2-{6-[((3S)oxolan-3-yl)amino]purin-9-yl}(4S,5S,2R,3R)-5-(4-pyridylthiomethyl)oxolane-3,4-diol;and5-{6-[((3R)oxolan-3-yl)amino]purin-9-yl}(2S,3R,4R,5R)-4-acetyloxy-2-[(4-fluorophenylthio)methyl]oxolan-3-yl]acetate.29. A method for modifying cardiac activity in a mammal experiencing aheart electrical disorder that can be treated by stimulating an A₁adenosine receptor comprising the administration of a therapeuticallyeffective amount of the composition of claim 1 to the mammal.
 30. Amethod for modifying mammalian adipocyte function by stimulating an A₁adenosine receptor comprising administering a therapeutically effectiveamount of the composition of claim 1 to the mammal.
 31. A method torestore sensitivity and efficacy of insulin in a mammal by stimulatingan A₁ adenosine receptor comprising the administration of atherapeutically effective amount of a composition of claim 1 to themammal.
 32. A method for providing a mammal with central nervous systemneuroprotection by stimulating an A₁ adenosine receptor comprisingadministering a therapeutically effective amount of the composition ofclaim 1 to the mammal.
 33. A method for providing a mammal withcardiomyocyte protection from ischemia by stimulating an A₁ adenosinereceptor comprising administering a therapeutically effective amount ofthe composition of claim 1 to the mammal.
 34. The method of claim 29 or30 or 31 or 32 or 33 wherein the therapeutically effective amount rangesfrom about 0.01 to about 100 mg/kg weight of the mammal.
 35. The methodof claim 29 wherein the composition is administered to the mammalexperiencing a heart electrical disorder selected from the groupconsisting of supraventricular tachycardias, atrial fibrillation, atrialflutter, and AV nodal re-entrant tachycardia.
 36. The method of claim 30or 31 wherein the composition is administered to a mammal experiencing adisorder selected from the group consisting of diabetes and obesity. 37.The method of claim 32 wherein the composition is administered to amammal experiencing an central nervous system disorder selected from thegroup consisting of epilepsy, and stroke.
 38. The method of claim 33wherein the composition is administered to a mammal experiencing anischemic event in the heart selected from the group consisting of stableangina, unstable angina, cardiac transplant, and myocardial infarction.39. The method of; claim 29 or 30 or 31 or 32 or 33 wherein the mammalis a human.
 40. A pharmaceutical composition of matter comprising thecomposition of claim 1 and one or more pharmaceutical excipients. 41.The pharmaceutical composition of matter of claim 40 wherein thepharmaceutical composition is in the form of a solution.
 42. Thepharmaceutical composition of matter of claim 40 wherein thepharmaceutical composition is in the form of a tablet.